SPARC Endogenous Level, rather than Fibroblast-Produced SPARC or Stroma Reorganization Induced by SPARC, Is Responsible for Melanoma Cell Growth

Abstract

SPARC (secreted protein acidic and rich in cysteine) is a matricellular protein whose overexpression in malignant or tumor-stromal cells is often associated with increased aggressiveness and bad prognosis in a wide range of human cancer types, particularly melanoma. We established the impact that changes in the level of SPARC produced by malignant cells and neighboring stromal cells have on melanoma growth. Melanoma cell growth in monolayer was only slightly affected by changes in SPARC levels. However, melanoma growth in spheroids was strongly inhibited upon SPARC hyperexpression and conversely enhanced when SPARC expression was downregulated. Interestingly, SPARC overexpression in neighboring fibroblasts had no effect on spheroid growth irrespective of SPARC levels expressed by the melanoma cells, themselves. Downregulation of SPARC expression in melanoma cells induced their rejection in vivo through a mechanism mediated exclusively by host polymorphonuclear cells. On the other hand, SPARC hyperexpression enhanced vascular density, collagen deposition, and fibroblast recruitment in the surrounding stroma without affecting melanoma growth. In agreement with the in vitro data, overexpression of SPARC in co-injected fibroblasts did not affect melanoma growth in vivo. All the data indicate that melanoma growth is not subject to regulation by exogenous SPARC, nor by stromal organization, but only by SPARC levels produced by the malignant cells themselves.

Persistent Activation of the Fyn/ERK Kinase Signaling Axis Mediates Imatinib Resistance in Chronic Myelogenous Leukemia Cells through Upregulation of Intracellular SPARC

“…This uncommon expression of SPARC is not specific to IM-R cells, as forced expression of full-length SPARC in IM-S K562 cells also leads to its retention inside the cells. In contrast, overexpression of SPARC in A375 melanoma cells is accompanied by accumulation in the culture medium (23). Thus, intracellular SPARC retention seems inherent in K562 cells.…”

“…4A). Interestingly, neither SPARC-WT nor SPARC-DS (or SPARC-DEC) was secreted in IM-S cells, whereas, as expected, SPARC-WT and SPARC-DEC were detected in the culture medium of melanoma cells (23).…”

“…Together, these reports indicate that SPARC might function intracellularly to influence diverse cellular activities. SPARC has been linked to the progression and invasive abilities of many solid tumors, such as prostate and breast cancers, and melanoma (21)(22)(23)(24), whereas it appears to have tumor-suppressing properties in ovarian cancers and certain myeloid malignancies (25,26).…”

Macrophage-Derived SPARC Bridges Tumor Cell-Extracellular Matrix Interactions toward Metastasis

“…In this regard, a study on glioma shows that downregulation of SPARC expression by short interfering RNA decreases tumor cell survival and invasion, reducing focal adhesion kinase and AKT activation (17). In contrast to ovarian cancer, melanoma is not influenced by host-derived SPARC (18).…”

Microenvironment and tumor progression of melanoma: New therapeutic prospectives

“…In contrast, an increase in SPARC expression has influenced cell growth, causing an increase in collagen deposition, vascular density, and a recruitment of stromal cells (Prada et al, 2007). The activity of SPARC protein isolated from melanoma cells has been assessed and compared with that isolated from different cell types, including insect cells; the results showed the capability of tumor SPARC to increase the proliferation of normal and transformed human endothelial cells (Haber et al, 2008).…”